Pharmaceutical compositions containing an N-[1-(ω-phenyl-alkyl) -piperidyl-4]-N- (α-pyridyl)-carboxylic acid amide and method of use

ABSTRACT

Pharmaceutical compositions containing as an active ingredient a compound of the formula ##SPC1## 
     Wherein 
     R is straight or branched alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 2 carbon atoms or phenyl, and 
     n is an integer from 2 to 4, inclusive, 
     Or a non-toxic, pharmacologically acceptable acid addition salt thereof; and a method of using the same as non-narcotic analgesics.

This is a division of copending application Ser. No. 497,455 filed Aug.14, 1974, now U.S. Pat. No. 3,933,832 granted Jan. 20, 1976.

This invention relates to novel pharmaceutical compositions containingan N-[1-(ω-phenyl-alkyl)-piperidyl-4]-N-(α-pyridyl)-carboxylic acidamide or a non-toxic acid addition salt thereof, as well as to a methodof using the same as non-narcotic analgesics.

BACKGROUND OF THE INVENTION

A class of 4-phenylamino-piperadines with strong analgesic activity isdisclosed in French Pat. No. M 2430 (C.A. 62, 14634), and U.S. Pat. No.3,141,823 discloses an analgesic and tranquilizing compositioncontaining one particular compound of that class, namelyN-(1-phenethyl-4-piperidyl)-propionanilide (generic name: Fentanyl), oncombination with droperidol. However, fentanyl, being a very strongmorphine-like analgesic, has a very substantial addition potential.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel pharmaceuticalcompositions containing an N-piperidyl-N-pyridyl-carboxamide.

It is another object of the present invention to provide novelpharmaceutical compositions having strong analgesic properties, but noaddiction potential.

Other objects and advantages of the invention will become apparent asthe description thereof proceeds.

THE INVENTION

The above objects are achieved by providing pharmaceutical compositionscontaining as an active ingredient an N-piperidyl-N-pyridyl-carboxamideof the formula ##SPC2##

Wherein

R is straight or branched alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 2carbon atoms or phenyl, and

n is an integer from 2 to 4, inclusive, or a non-toxic,pharmacologically acceptable acid addition salt thereof.

The compounds embraced by formula I above may be prepared by thefollowing methods:

Method A

Acylation of a 1-phenylalkyl-4-[N-(α-pyridyl)-amino]-piperidine of theformula ##SPC3##

Wherein n has the meanings defined above, with an acylating agent of theformula ##STR1## wherein R has the same meanings as in formula I, and

X is halogen or R--COO--, where R has the meanings previously defined.

The reaction is advantageously performed in a non-hydrolizing, organicsolvent, and preferably in the presence of an acid-binding agent. Thereaction temperature is variable within wide limits, namely between roomtemperature and the boiling point of the reaction mixture.

METHOD B

Reaction of a piperidyl-(4)-N-(α-pyridyl)-carboxylic acid amide of theformula ##SPC4##

Wherein R has the same meanings as in formula I, with an alkylatingagent of the formula ##SPC5##

wherein

n has the meanings previously defined and

Y is halogen, arylsulfonyloxy or alkylsulfonyloxy.

The alkylation is effected with the calculated quantity or a slightexcess of the alkylating agent. It is advantageous to alkylate in thepresence of an acid-binding agent and an inert solvent or mixture ofsolvents. The reaction temperature is variable within wide limits;temperatures between 0° C and the boiling point of the solvent ormixture of solvents are preferred.

The starting compounds of the formula II are prepared by reactingα-chloro-pyridine with 4-amino-1-benzyl-piperidine in the presence ofcooper powder to form 4-[N-(α-pyridyl)-amino]-1-benzyl-piperidine of theformula ##SPC6##

debenzylating the compound of the formula VI, and subsequentlyalkylating the debenzylation product.

Compounds of the formula IV are obtained, starting from a compound ofthe formula VI, by acylation and subsequent debenzylation.

The compounds embraced by formula I are organic bases and therefore formacid addition salts with inorganic or organic acids. Examples ofnon-toxic, pharmacologically acceptable acid addition salts are thoseformed with hydrochloric acid, hydrobromic acid, hydroidic acid,hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, aceticacid, propionic acid, butyric acid, valeric acid, pivalic acid, caproicacid, capric acid, oxalic acid, malonic acid, succinic acid, maleicacid, fumaric acid, lactic acid, citric acid, malic acid, benzoic acid,phthalic acid, cinnamic acid, salicylic acid, p-hydroxybenzoic acid,ascorbic acid, 8-chlorotheophilline, methanesulfonic acid,ethanephosphonic acid or the like.

The following examples illustrate the preparation of various compoundsof the formula I and their non-toxic acid addition salts.

Preparation of starting compounds:

EXAMPLE A 4-[N-(α-Pyridyl)-amino]-1-phenethyl-piperidine a.4-[N-α-pyridyl-amino]-1-benzyl-piperidine

A mixture consisting of 79.2 gm (0.7 mol) of 2-chloropyridine, 380.4 gm(2 mols) of 4-amino-1-benzyl-piperidine and 45.9 gm (0.75 gm-atom) ofcooper powder was stirred for 20 hours at an internal temperature of180° C. Thereafter, the reaction mixture was allowed to cool, the darkoil was dissolved in 750 ml of 6 N hydrochloric acid, the resultingsolution was admixed with 50 gm of activated charcoal, and the mixturewas briefly heated and then vacuum-filtered through 20 gm ofdiatomaceous earth while hot. The filtrate was cooled and then adjustedto pH 4.5- 5.0 with aqueous 30% sodium hydroxide, and this solution(phase 1) was extracted three times with 100 ml of methylene chlorideeach (phase 2). The aqueous phase 1 was now adjusted to pH 8 withaqueous 30 % sodium hydroxide and then extracted four times with 150 mlof ether each (phase 3). The ethereal phase 3 was extracted twice withwater, dried and evaporated; the two aqueous extracts were combined(phase 4) and set aside for recovery of the 4-amino-1-benzyl-piperidinestarting compound. The evaporation of the ethereal phase 3 left as aresidue 127 gm of raw reaction product having a melting point of90°-100° C, which was recrystallized once from petroleum ether (b.p.80°-110° C), yielding 78.3 gm (55.7% of theory) of4-[N-(α-pyridyl)-amino]-1-benzyl-pyridine, m.p. 106°-107° C.

Recovery of starting compounds:

The methylene chloride extracts (phase 2) were washed with water, driedand evaporated, leaving 20 gm of 2-chloro-pyridine.

The combined aqueous extracts (phase 4) were saturated with causticsoda, whereupon most of the unreacted, oily 4-amino-1-benzyl-piperidinecontained therein precipitated out and was separated. The aqueous motherliquor was once again extracted with methylene chloride, the organicextract was combined with the 4-amino-1-benzyl-piperidine alreadyrecovered, the methylene chloride was evaporated, and the residue wasdistilled in a high vacuum over solid potassium hydroxide. Thus a totalof 228 gm of 4-amino-1-benzyl-piperidine, b.p. 96°-100° C at 0.2 mm Hg,were recovered, which corresponded to about 60% of the amount originallyused.

b. 4-[N-(α-pyridyl)-amino]-piperidine and its hydrochloride

A solution of 26.7 gm (0.1 mol) of4-[N-(α-pyridyl)-amino]-1-benzyl-piperidine in 500 ml of ethanol wasadmixed with 5 gm of palladized (10%) charcoal, and the mixture washydrogenated at 60° C and 5 atmospheres pressure until the calculatedamount of hydrogen for debenzylation had been absorbed. Thereafter, thecatalyst was vacuum-filtered off, the filtrate was evaporated, and theresidue was recrystallized from ethyl acetate, yielding 19.5 gm (91% oftheory) of 4-[N-(α-pyridyl)-amino]-piperidine, m.p. 158°-161° C.

c. A mixture consisting of 1.77 gm (0.01 mol) of4-[N-(α-pyridyl)-amino]-piperidine, 2.04 gm (0.011 mol) of 2-phenethylbromide, 1.26 gm (0.015 mol) of sodium bicarbonate and 25 ml of amixture of tetrahydrofuran and dimethylformamide (3:1) was refluxed for5 hours. After cooling, the solvent mixture was evaporated, and theresidue was extracted several times with chloroform. The combinedchloroform extracts were extracted five times with water, dried andevaporated, the residual oil was dissolved in 20 ml of ethanol, thesolution was acidified with 2 ml of 5 N ethanolic hydrochloric acid, andether was added until crystallization commenced. 2.3 gm (72.3% oftheory) of 4-[N-(α-pyridyl)-amino]-1-phenethyl-piperidine hydrochloride,m.p. 223°-225° C, crystallized out.

EXAMPLE B 4-[N-(α-pyridyl)-N-propionyl-amino]-piperidine hydrochloridea. 4-[N-(α-pyridyl)-N-propionyl-amino]-1-benzyl-piperidine

A mixture consisting of 2.67 gm (0.01 mol) of4-[N-(α-pyridyl)-amino]-1-benzyl-piperidine and 6 gm of propionic acidanhydride was refluxed for 90 minutes. Thereafter, the excess, unreactedanhydride was evaporated in vacuo, and the residue was poured into amixture of 100 gm of ice and 20 ml of concentrated ammonia. Theresulting aqueous suspension was extracted three times with 100 ml ofmethylene chloride each, the combined organic extracts were dried oversodium sulfate and then evaporated, and the residue was recrystallizedfrom ethanol. 2.8 gm of4-[N-(α-pyridyl)-N-propionyl-amino]-1-benzyl-piperidine, m.p. 90°-93° C,were obtained.

b. 3.23 gm (0.01 mol) of4-[N-(α-pyridyl)-N-propionyl-amino]-1-benzyl-piperidine were convertedin conventional manner into the monohydrochloride, which was thendissolved in 50 ml of ethanol. After addition of 5 gm of palladizedcharcoal the mixture was hydrogenated at 20° C and 5 atmospherespressure until the calculated amount of hydrogen for debenzylation hadbeen absorbed. Thereafter, the catalyst was removed by vacuumfiltration, the filtrate was evaporated, and the residue wasrecrystallized from ethanol/ether. 2.56 gm (95% of theory) of4-[N-(α-pyridyl)-N-propionyl-amino]-piperidine hydrochloride, m.p.221°-222° C, were obtained.

Preparation of end products of the formula I:

EXAMPLE 14-[N-(α-Pyridyl)-N-(ethoxycarbonyl)-amino]-1phenethyl-piperidine and itshydrochloride by method A

A mixture consisting of 2.81 gm (0.01 mol) of4-[N-(α-pyridyl)-amino]-1-phenethyl-piperidine, 15 ml of chloroform, 2ml of pyridine and 5.36 gm (0.05 mol) of ethyl chloroformate wasrefluxed for 24 hours. Thereafter, the reaction solution was allowed tocool and was then poured over 500 gm of ice while adding 50 ml ofconcentrated ammonia thereto. The resulting aqueous mixture was thenextracted five times with 50 ml of chloroform each, the combined organicextracts were washed with water, dried over sodium sulfate andvacuum-filtered, and the solvent was evaporated from the filtrate. Theoily residue,4-[N-(α-pyridyl)-N-(ethoxycarbonyl)-amino]-1-phenethyl-piperidine, wasdissolved in 20 ml of ethanol, the solution was made weakly acid with 2ml of 5 N ethanolic hydrochloric acid, then ether was carefully addeduntil precipitation commenced, and the precipitate was collected. 2.5 gm(64.2% of theory) of the hydrochloride, m.p. 183°-186° C, of the formula##SPC7##

were obtained.

EXAMPLE 2 4-[N-(α-Pyridyl)-N-propionyl-amino]-1-phenethyl-piperidine andits hydrochloride by method B

A mixture consisting of 2.69 (0.01 mol) of4-[N-(α-pyridyl)-N-propionyl-amino]-piperidine hydrochloride, 2.4 gm(0.011 mol) of 2-phenethyl bromide, 2.52 gm (0.03 mol) of sodiumbicarbonate and 25 ml of a mixture of tetrahydrofuran anddimethylformamide (3:1) was refluxed for 4 hours. Thereafter, 100 ml ofmethylene chloride were added to the reaction mixture, and the resultingsuspension was extracted five times with 100 ml of water each. Theorganic phase was dried over sodium sulfate, the solvent was evaporated,and the oily residue,4-[N-(α-pyridyl)-N-propionyl-amino]-1-phenethyl-piperidine, wasdissolved in 20 ml of ethanol. The resulting solution was made weaklyacid with 2 ml of 5 N ethanolic hydrochloric acid, and then ether wasadded until crystallization commenced. The crystalline product wascollected, yielding 1.95 gm (52% of theory) of the hydrochloride, m.p.217°-221° C. of the formula ##SPC8##

EXAMPLE 3

Using a procedure analogous to that described in Example 2, 57% oftheory of 4-[N-(α-pyridyl)-N-acetyl-amino]-1-phenethyl-piperidine, m.p.83°-84° C, of the formula ##SPC9##

was obtained from 4-[N-(α-pyridyl)-N-acetyl-amino]-piperidine and2-phenethyl bromide.

EXAMPLE 4

Using a procedure analogous to that described in Example 2, 62% oftheory of 4-[N-(α-pyridyl)-N-(n-butyryl)-amino]-1-phenethyl-piperidineand its hydrochloride, m.p. 208°-209° C, of the formula ##SPC10##

was obtained from 4-[N-(α-pyridyl)-N-(n-butyryl)-amino]-piperidine and2-phenethyl bromide.

EXAMPLE 5

Using a procedure analogous to that described in Example 2, 53% oftheory of 4-[N-(α-pyridyl)-N-isobutyryl-amino]-1-phenethyl-piperidineand its hydrochloride, m.p. 219°-220° C, of the formula ##SPC11##

was obtained from 4-[N-(α-pyridyl)-N-isobutyryl-amino]-piperidine and2-phenethyl bromide.

EXAMPLE 6

Using a procedure analogous to that described in Example 2, 67% oftheory of 4-[N-(α-pyridyl)-N-benzoyl-amino]-1-phenethyl-piperidine andits hydrochloride, m.p. 235°-240° C, of the formula ##SPC12##

was obtained from 4-[N-(α-pyridyl)-N-benzoyl-amino]-piperidine and2-phenethyl bromide.

EXAMPLE 7

Using a procedure analogous to that described in Example 1, 24% oftheory of4-[N-pyridyl)-N-propionyl-amino]-1-(γ-phenyl-n-propyl)-piperidine andits hydrochloride, m.p. 119°-124° C, of the formula ##SPC13##

was obtained from4-[N-(α-pyridyl)-amino]-1-(γ-phenyl-n-propyl)-piperidine and propionylchloride.

EXAMPLE 8

Using a procedure analogous to that described in Example 1, 32% oftheory of4-[N-(α-pyridyl)-N-(propionyl)-amino]-1-(4'-phenyl-n-butyl)-piperidineand its hydrochloride, m.p. 189°-191° C, of the formula ##SPC14##

was obtained from4-[N-(α-pyridyl)-amino]-1-(4'-phenyl-n-butyl)-piperidine and propionylchloride.

The compounds embraced by formula I above and their non-toxic,pharmacologically acceptable acid addition salts, have usefulpharmacodynamic properties; more particularly, they exhibit stronganalgesic activity in warm-blooded animals, such as mice and rats, withpractically no morphine-like side effects, such as respirationdepression, Straub's tail or the like.

For pharmaceutical purposes, the compounds of the formula I or theirnon-toxic acid addition salts are administered to warm-blooded animalsenterally or parenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. The effective oral dosage unit range of thecompounds of the formula I and their non-toxic acid addition salts isfrom 0.16 to 5.0 mgm/kg body weight, preferably 0.83 to 2.5 mgm/kg bodyweight; the parenteral dosage unit range is about 0.5 to 1.67 mgm/kgbody weight.

The following examples illustrate a few pharmaceutical dosage unitcompositions comprising a compound of the formula I or a non-toxic acidaddition salt thereof as an active ingredient and represent the bestmodes contemplated of putting the invention into practical use. Theparts are parts by weight unless otherwise specified.

EXAMPLE 9

Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        4-[N-(α-pyridyl)-N-ethoxycarbonyl)-amino]-                              1-phenethyl-piperidine hydrochloride                                                                   50.0 parts                                           Lactose                  95.0  "                                              Corn starch              45.0  "                                              Colloidal silicic acid   2.0  "                                               Soluble starch           5.0  "                                               Magnesium stearate       3.0  "                                               Total                    200.0 parts                                          ______________________________________                                    

Preparation:

The active ingredient is admixed with part of the excipients, and themixture is granulated with a solution of the soluble starch in water.After drying of the granulate, the remaining excipients are admixed withit, and the mixture is compressed into 200 mgm-tablets. Each tabletcontains 50 mgm of the piperidine compound and is an oral dosage unitwith very effective analgesic action.

EXAMPLE 10

Coated pills

The pill core composition is compounded from the following ingredients:

    ______________________________________                                        4-[N-(α-pyridyl)-N-(propionyl)-amino]-                                  1-phenethyl-piperidine hydrochloride                                                                   75.0 parts                                           Lactose                  100.0  "                                             Corn starch              65.0  "                                              Colloidal silicic acid   2.0  "                                               Soluble starch           5.0  "                                               Magnesium stearate       3.0  "                                               Total                    250.0 parts                                          ______________________________________                                    

Preparation:

The ingredients are compounded as described in Example 9, and thecomposition is compressed into 250 mgm-pill cores which are subsequentlycoated in conventional manner with a thin shell consisting essentiallyof a mixture of sugar, talcum and gum arabic. Each coated pill contains75 mgm of the piperidine compound and is an oral dosage unit compositionwith very effective analgesic action.

EXAMPLE 11

Suppositories

The suppository composition is compounded from the followingingredients:

    ______________________________________                                        4-[N-(α-pyridyl)-N-(ethoxycarbonyl)-amino]-                             1-phenethyl-piperidine hydrochloride                                                                    50.0 parts                                          Lactose                   250.0  "                                            Suppository base (e.g. cocoa butter)                                                                    1400.0  "                                           Total                     1700.0 parts                                        ______________________________________                                    

Preparation:

The active ingredient and the lactose are intimately admixed with eachother, and the mixture is homogeneously blended in the moltensuppository base. 1700 mgm-portions of the composition are poured intocooled suppository molds and allowed to harden therein. Each suppositorycontains 50 mgm of the piperidine compound and is a rectal dosage unitcomposition with very effective analgesic action.

Analogous results are obtained when any one of the other compoundsembraced by formula I or a non-toxic, pharmacologically acceptable acidaddition salt thereof is substituted for the particular piperidinecompound in Examples 9 through 11. Likewise, the amount of activeingredient in these illustrative examples may be varied to achieve thedosage unit range set forth above, and the amounts and nature of theinert pharmaceutical carrier ingredients may be varied to meetparticular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. An analgesic pharmaceutical dosage unit compositionconsisting essentially of an inert pharmaceutical carrier and aneffective analgesic amount of a compound of the formula ##SPC15##whereinR is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 2 carbon atoms orphenyl, and n is an integer from 2 to 4, inclusive,or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 2. Acomposition of claim 1, where said compound is4-[N-(α-pyridyl)-N-benzoyl-amino]-1-phenethyl-piperidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 3. Acomposition of claim 1, where said compound is4-[N-(α-pyridyl)-N-propionyl-amino]-1-phenethyl-piperidine or anon-toxic, pharmacologically acceptable acid addition salt thereof. 4.The method of raising the pain threshold of a warm-blooded animal, whichcomprises administering to said animal an effective analgesic amount ofa compound of the formula ##SPC16##wherein R is alkyl of 1 to 3 carbonatoms, alkoxy of 1 to 2 carbon atoms or phenyl, and n is an integer from2 to 4, inclusive,or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 5. The method of claim 4, where said compound is4-[N-(α-pyridyl)-N-benzoyl-amino]-1-phenethyl-piperidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 6. The methodof claim 4, where said compound is4-[N-(α-pyridyl)-N-propionyl-amino]-1-phenethyl-piperidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.